Oncogene
SEARCH     advanced search my account e-alerts subscribe register
Journal home
Advance online publication
Current issue
Archive
Press releases
For authors
For referees
Contact editorial office
About the journal
For librarians
Subscribe
Advertising
naturereprints
Contact NPG
Customer services
Site features
NPG Subject areas
Access material from all our publications in your subject area:
Biotechnology Biotechnology
Cancer Cancer
Chemistry Chemistry
Dentistry Dentistry
Development Development
Drug Discovery Drug Discovery
Earth Sciences Earth Sciences
Evolution & Ecology Evolution & Ecology
Genetics Genetics
Immunology Immunology
Materials Materials Science
Medical Research Medical Research
Microbiology Microbiology
Molecular Cell Biology Molecular Cell Biology
Neuroscience Neuroscience
Pharmacology Pharmacology
Physics Physics
Browse all publications
 
26 February 1998, Volume 16, Number 8, Pages 1021-1030
Table of contents    Previous  Abstract  Next   Article  PDF
Article
The DNA binding domains of the WT1 tumor suppressor gene product and chimeric EWS/WT1 oncoprotein are functionally distinct
Jungho Kim1, Kevin Lee2 and Jerry Pelletier1,3,a

1Department of Biochemistry, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6

2Department of Biology, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong

3Department of Oncology, McGill University, 3655 Drummond Street, Montreal, Quebec, Canada, H3G 1Y6

aAuthor for correspondence:

Abstract

The t(11; 22)(p13; q12) translocation associated with desmosplastic small round cell tumor results in a chimeric molecule fusing the amino terminal domain (NTD) of the EWS1 gene to three of the four carboxy-terminal zinc fingers of the WT1 tumor suppressor gene. Since the DNA binding domains of WT1 and EWS/WT1 are structurally different, we have assessed the functional consequences of the EWS/WT1 fusion. We find that the EWS/WT1 protein has a higher binding affinity for a given recognition target than the WT1 product. This is unlike other fusion products involving translocation of the NTD of EWS to DNA binding domains in which DNA binding specificity and affinity is not changed. We demonstrate that EWS/WT1 is a nuclear protein and that the NTD of EWS contains (a) nuclear localization signal(s). We also find that the integrity of a domain within the WT1 zinc fingers, responsible for mediating interaction between WT1 and the transcriptional repressor par-4, is disrupted in the EWS/WT1 fusion product. Deletion analysis of the NTD of EWS indicated that integrity of the entire domain was necessary to achieve full transactivation potential.

Keywords

EWS/WT1; DSRCT; oncogene; cancer genetics; transcription factor

Received 20 June 1997; accepted 3 October 1997
26 February 1998, Volume 16, Number 8, Pages 1021-1030
Table of contents    Previous  Abstract  Next   Article  PDF